Galanin is a neuropeptide believed to promote food intake and fat deposition via a dietary fat-dependent positive feed-forward mechanism, a salient property given the spread of obesity with the rise of Western diets. However, the physiologic and therapeutic relevance of galanin systems for overeating and fat accrual has remained uncertain because the proper tools to define its endogenous role and mediating receptor subtype, behavioral mechanism and neuroanatomical sites of action were not available. The present application seizes upon a convergence of molecular, pharmacological and behavioral advances to determine how galanin systems increase food intake and promote adiposity when palatable diets are present. Aim 1 identifies the galanin receptor (GalR) subtype that mediates orexigenic and metabolic actions of galanin through complementary approaches: acute intracranial infusion of galanin in GalR deficient mice and acute intracranial infusion of recently available subtype-preferring agonists and antagonists. The physiologic role of endogenous galanin signaling in facilitating hyperphagia and obesity will be studied in mutant GalR knockout mice with long-term access to diets high or low in saturated fat. Aim 2 uses concentration-response analysis of intake/preference curves, microstructure and progressive ratio analyses, and experimental manipulation of post-oral feedback to identify the behavioral mechanism underlying galanin system modulation of intake. Aim 3 combines functional mapping approaches and local short hairpin RNA (shRNA) knockdown of GalR gene expression to identify, with molecular and neuroanatomical specificity, brain targets through which galanin has orexigenic action. Persistent, local knockdown of GalR expression also will test the physiologic influence of endogenous hypothalamic GalR systems on food intake, metabolism, and adiposity with both brain region- and molecular-specificity. Results from the project will help define the physiologic role and molecular, behavioral and neuroanatomical modes of action by which galanin promotes obesity in the presence of palatable, high-fat food. Targeted therapies against these activities could then potentially be devised. PUBLIC HEALTH RELEVANCE About 1 billion people worldwide are overweight or obese, cutting across age, race, ethnicity and gender, and these conditions increase mortality, morbidity, and economic costs. Galanin is a neuropeptide that promotes food intake and fat deposition in rodents and which is associated with obesity risk. In this proposal, we begin to identify the behavioral, anatomical, and receptor mechanisms of action by which galanin promotes food intake. The functional significance of galanin receptor signaling in obesity risk and overeating in the presence of palatable diets also will be determined. By increasing our understanding of this understudied molecular control of energy homeostasis, the results may lead to new preventative or therapeutic options for obesity and will increase our understanding of the neurobiology of appetite.